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Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Summary

Background

Intravenous administration of a third-generation cephalosporin is optimal antibiotic treatment for spontaneous bacterial peritonitis.

Aims

To compare an intravenous–oral step-down schedule with ciprofloxacin (switch therapy) to intravenous ceftazidime in the treatment of spontaneous bacterial peritonitis, and to evaluate the impact of terlipressin and albumin in the treatment of type 1 hepatorenal syndrome on mortality.

Methods

A total of 116 cirrhotic patients with spontaneous bacterial peritonitis, were randomly given switch therapy with ciprofloxacin (61 patients) or intravenous ceftazidime (55 patients). All patients who developed type 1 hepatorenal syndrome were treated with terlipressin (2–12 mg/day) and albumin (20–40 g/day).

Results

Resolution of infection was achieved in 46/55 patients treated with ceftazidime (84%) and in 49/61 patients treated with ciprofloxacin (80%, P = N.S.). An intravenous–oral step-down schedule was possible in 50/61 patients (82%) who received ciprofloxacin; 45/61 patients (74%) were discharged before the end of antibiotic treatment and completed it at home. The mean saving per patient due to the reduction of hospital stay in the ciprofloxacin group was 1150 €. Type 1 hepatorenal syndrome was treated successfully in 12/19 patients (63%). As a consequence, the in-hospital mortality rate due to infection was 10%.

Conclusions

Switch therapy with cephalosporin is more cost-effective than intravenous ceftazidime in the treatment of spontaneous bacterial peritonitis in cirrhotic patients who are not on prophylaxis with quinolones.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Spontaneous bacterial peritonitis (SBP) is a serious complication occurring in 10–30% of hospitalized cirrhotic patients with ascites.1–8 The gold standard of antibiotic treatment in patients with SBP is the intravenous administration of third-generation cephalosporin.9–15 Several studies have shown that the use of intravenous antibiotics initially, followed by oral step-down administration (switch therapy) is also effective.16, 17 Terg et al. showed that switch therapy with ciprofloxacin is effective in complicated and uncomplicated SBP treatment, although in this study there was no comparison with an intravenous third-generation cephalosporin.17 Navasa et al. observed that the oral administration of ofloxacin had similar efficacy to intravenous cefotaxime, although this study included only patients with uncomplicated SBP.18 In a recent pilot study, oral ciprofloxacin was shown to be as effective as cefotaxime and ceftriaxone in the treatment of SBP.19 Despite all these observations there is no controlled clinical trial comparing switch therapy with ciprofloxacin to intravenous administration of a third-generation cephalosporin. Therefore, up to now, the potential advantages of switch therapy on intravenous third-generation cephalosporin in the treatment of SBP, most notably the reduction in the length of hospital stay, has only been hypothesized.

Almost one-third of cirrhotic patients with ascites and SBP develop type 1 hepatorenal syndrome (HRS).20, 21 SBP is therefore considered the most common precipitating factor of type 1 HRS.22 Type 1 HRS is thought to be caused by the further decrease in effective arterial blood volume due to the infection itself.23, 24 HRS can be effectively prevented by giving intravenous albumin together with antibiotic treatment.25 In the last few years, the use of vasoconstrictors such as ornipressin, terlipressin,26–29 noradrenaline or midodrine,30,31 together with intravenous albumin, has achieved promising results in the treatment of HRS.32, 33 Nevertheless, their impact on type 1 HRS induced by SBP is still subject to debate.29, 34

Consequently, the aims of the study were: (i) to compare switch therapy with ciprofloxacin to intravenous ceftazidime in the treatment of SBP, both in terms of efficacy and cost; and (ii) to evaluate the effects of treatment with terlipressin and albumin in patients with SBP-induced type 1 HRS.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Patients

A total of 116 patients were included in this multicentre, randomized-controlled trial which set out to compare the efficacy of two antibiotic treatments of SBP. Trial was carried out in four hospitals in the north-east of Italy and was approved by the ethical committee of each hospital. Patients gave written informed consent to their participation. Inclusion criteria were: (i) diagnosis of cirrhosis with ascites and (ii) diagnosis of SBP. The diagnosis of SBP was based on a polymorphonuclear (PMN) count in ascitic fluid of >250/mm3 in the absence of clinical and radiological findings suggestive of secondary peritonitis.

Exclusion criteria were: (i) antibiotic treatment, including prophylactic treatment with quinolones, within 1 month of inclusion; (ii) history of hypersensitivity to quinolones or β-lactam antibiotics; (iii) age <18 and >75 years; (iv) evidence of other bacterial or fungal infections; (v) evidence of organic nephropathy (proteinuria, haematuria or abnormal findings on renal ultrasonography) and (vi) presence of shock, gastrointestinal (GI) bleeding, dehydration, hepatocellular carcinoma, cardiac failure, extrahepatic neoplasia at the diagnosis of SBP.

A total of 165 consecutive patients with cirrhosis and ascites with SBP were evaluated. Of these, 49 patients were excluded from the study for the following reasons: hepatocellular carcinoma (16 patients), treatment with antibiotics at diagnosis of SBP (nine), organic nephropathy (five), GI bleeding (five), age >75 years (three), hypersensitivity to β-lactam antibiotics (two), cardiac failure (two), extrahepatic neoplasia (two), other bacterial infections (two) and cardiac failure (three). Of 116 patients who were included in the study, 55 were randomly assigned to intravenous ceftazidime while 61 were assigned to switch therapy with ciprofloxacin.

Protocol

Physical examination, chest and abdominal radiography, abdominal ultrasonography and routine laboratory tests were performed in all patients before starting the antibiotic therapy. In addition, samples of at least 60 mL of ascitic fluid and 20 mL of blood were taken for culture and other laboratory examinations at the patients’ bedside. Fresh urine sediment and a urine culture were also performed. Ascitic fluid PMN cell count and culture were repeated 48 h and 7 days after starting treatment. At least 20 mL of ascitic fluid were injected into two blood culture bottles (10 mL each). Patients discharged before the end of antibiotic treatment underwent these diagnostic procedures as out-patients.

Randomization was performed with sealed envelopes containing the treatment options prepared with random numbers generated by the statistica 6.1 software (StatSoft, Inc. 1984–2004, Tulsa, OK, USA). Randomization was independent for each hospital.

Intravenous ceftazidime (Spectrum, Sigma-Tau Sp.A., Pomezia, Rome, Italy) was administered at doses of 2 g b.d., 1 g b.d. and 1 g at every 24 h for serum creatinine levels of <1.5 mg/dL, 1.5–2.5 mg/dL, and >2.5 mg/dL respectively. Intravenous ciprofloxacin (Ciproxin, Bayer Sp.A., Milan, Italy) was administered at doses of 200 mg b.d. and 200 mg at every 24 h for serum creatinine levels of 2.5 mg/dL and >2.5 mg/dL respectively. Intravenous ciprofloxacin was followed by oral ciprofloxacin if and when clinical signs of infection (fever, abdominal pain, ileus, hepatic encephalopathy) had disappeared, PMN count in the ascitic fluid and in blood had significantly decreased (more than 50% of the baseline value). Oral ciprofloxacin (Ciproxin, Bayer Sp.A. Milan, Italy) was administered at doses of 500 mg b.d. and 250 mg b.d. for serum creatinine levels of 2.5 mg/dL and >2.5 mg/dL respectively. After the randomization patients received ceftazidime or cipropfloxacin for 8 days, resolution of SBP was established when all clinical signs of the infection (fever, abdominal pain, ileus, hepatic encephalopathy) had disappeared, PMN count in the ascitic fluid had decreased to a value lower than 250/mm3, total and differential white blood cell count had normalized, and ascitic fluid cultures were negative. In patients who did not respond to ceftazidime or ciprofloxacin, the antibiotic treatment was modified according to the in vitro susceptibility of the isolated organism or was modified empirically in patients with negative blood, urine and ascitic fluid cultures.

Treatment failure was considered whenever any of the following phenomena occurred: (i) no positive therapeutic response; (ii) recurrence of infection caused by the same organism within 1 month of the end of the assigned antibiotic treatment; (iii) superinfection caused by organisms resistant to the assigned antibiotic during treatment or within 1 month of its end and (iv) severe side-effects (i.e. allergic reactions, diarrhoea, dizziness, seizures).

In patients without renal failure at inclusion, renal impairment was diagnosed when the blood serum urea or serum creatinine level increased by more than 50% of the pre-treatment value, to levels higher than 50 mg/dL and 1.5 g/dL respectively. In patients with pre-existing renal failure, an increase in the blood urea nitrogen or serum creatinine level of more than 50% from baseline was required for a diagnosis of renal impairment. Type 1 HRS was diagnosed in patients who developed progressive renal failure despite the resolution of the SBP and had shown a final serum creatinine level of 2.5 mg/dL without any response to diuretic withdrawal and volume expansion by means of 1.5 L of isotonic saline solution, with proteinuria <500 mg/day, and with a normal renal ultrasound examination.35 Patients with type 1 HRS were fitted with a central venous line, a short peripheral intravenous catheter and a urinary bladder catheter. Terlipressin (Glypressin, Ferring Sp.A., Milan, Italy) was then given by continuous intravenous infusion starting with a dose of 2 mg/day. If no significant reduction in serum creatinine (≥30%) was observed, the dose was increased every 2 days in a stepwise manner to 4, 6, 8 and 12 mg/day. In addition to terlipressin, albumin (Kedrion Sp.A., Barga, Lucca, Italy) was given at a dose of 20–40 g/day in all patients to maintain central venous pressure between 12 and 14 cm H2O. Terlipressin and albumin were administered until the reversal of type 1 HRS or for a maximum of 15 days. Decrease of serum creatinine to <1.5 mg/dL was considered a complete response, while a decrease ≥50% of the peak creatinine value to a final value >1.5 mg/dL was considered a partial response to treatment for type 1 HRS. Patients were not given diuretics during the treatment of type 1 HRS. Patients who showed a complete or partial response to the treatment received diuretics as far as they were tolerated. Those patients with type 1 HRS as well as patients with type 2 HRS developing large ascites during the period of the study were treated with large volume paracentesis and albumin according to the International Ascites Club's guidelines on the management of ascites in cirrhosis.36 All patients included in the protocol were followed until death, liver transplantation or until 3 months after inclusion.

Statistical analysis

According to the current literatures17–19 we hypothesized similar efficacy for both antibiotic treatment regimens for SBP. The end point chosen to calculate the sample size was therefore the possibility of discharging patients before the end of antibiotic treatment (early discharge), taking into account that (i) an out-patient parenteral antibiotic treatment is not widely available and (ii) a third-generation cephalosporin is not available in both intravenous and oral formulations. Therefore, assuming that the possibility of an early discharge may occur in 25% of patients in the ciprofloxacin group and in no patient in the ceftazidime group, a minimum of 50 patients per group was required, with a two-sided type I error rate of 5% and a type II error rate of 20%.

The costs of antibiotic treatment and of hospital stay were calculated for each patient taking into account: (i) the type of antibiotic treatment, (ii) the presence of complications (type 1 HRS, hepatic encephalopathy and GI bleeding) during the stay in the Hepatology or Gastroenterology Unit and (iii) the stay in intensive care unit.

The results were analysed by a central coordinating committee at the Department of Clinical and Experimental Medicine at the University of Padova. Results were presented as mean ± S.E. Comparisons between groups were performed using the chi-square test or Fischer's exact test for categorical data, and Student's t-test for continuous data. Univariate analysis was used to identify factors predicting 3-month survival in patients with type 1 HRS. Variables reaching statistical significance in univariate analysis were subsequently included in multivariate analysis, by stepwise logistic regression, in order to identify independent predictors of the end point. Then, the survival functions were plotted according to the median value of the independent predictor variables. Statistical analyses were performed by using the statistica 6.1 software (StatSoft, Inc.). The P-values of <0.05 were considered significant.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Patient characteristics

Diagnosis of cirrhosis was based on liver biopsy in 85 patients and on clinical and ultrasonographic data in the remaining 21 patients. Table 1 summarizes the data in patients randomized to receive intravenous ceftazidime or switch therapy with ciprofloxacin. There were no significant differences between the two groups as far as the clinical presentation and aetiology of SBP were concerned.

Table 1.  Baseline features of the 116 patients according to the assigned antibiotic treatment
 Ceftazidime (n = 55)Ciprofloxacin (n = 61)
  1. aSerum urea level >50 mg/dL or serum creatinine level >1.5 mg/dL at the diagnosis of SBP.

  2. P < 0.025 in the comparison between the two groups.

  3. SBP, spontaneous bacterial peritonitis; MELD, model of end stage liver disease.

Age59 ± 1.260 ± 1.2
Sex (M/F)33/2235/26
Aetiology of cirrhosis, n (%)
 Alcohol-related24 (44)31 (51)
 Virus-related26 (47)28 (46)
 Other causes5 (9.1)2 (3.3)
Clinical features of SBP, n (%)
 Fever37 (67)40 (66)
 Abdominal pain34 (62)33 (54)
 Ileus 7 (13)9 (15)
 Hepatic encephalopathy22 (40)25 (41)
 Renal failurea26 (47)27 (44)
 Community acquired SBP35 (64)40 (66)
Aetiology of SBP
 Positive culture, n (%)31 (56)34 (56)
 Gram-negative bacilli, n (%)29 (94)32 (94)
 Escherichia coli2226
 Acinetobacter freundii34
 Pseudomonas aeruginosa21
 Others21
 Gram-positive cocci, n (%)2 (6.5)2 (5.9)
 In vitro susceptibility to the assigned antibiotic, n (%)30/31 (97)32/34 (94)
Laboratory features
 Polymorphonuclear leucocytes in peripheral blood (cells/mm3)7388 ± 6267704 ± 616
 Polymorphonuclear leucocytes in ascitic fluid (cells/mm3)1133 ± 144956 ± 68
 Haematocrit (%)33 ± 0.634 ± 0.5
 Serum bilirubin (mg/dL)4.3 ± 0.44.7 ± 0.4
 Serum albumin (g/dL)2.7 ± 0.52.9 ± 0.6
 Prothrombin activity (%)49 ± 2.043 ± 1.4*
 Serum urea (mg/dL)56 ± 4.257 ± 4.4
 Serum creatinine (mg/dL)1.3 ± 0.11.3 ± 0.1
Other features
 Child-Pugh classification (B/C)11/449/52
 Child-Pugh score11 ± 0.211 ± 0.2
 MELD score19 ± 0.817 ± 0.8
 Heart rate (beats/min)81 ± 1.078 ± 0.9
 Mean arterial pressure (mmHg)90 ± 0.992 ± 1.0

Resolution of infection

Resolution of infection was achieved with the initial antibiotic treatment in 46 of the 55 patients treated with ceftazidime (84%) and in 49 of 61 patients treated with ciprofloxacin (80%, P = N.S.). The causes of failure of the initial antibiotic treatment are shown in Table 2. Antibiotic treatment was changed in 15 of the 21 patients in whom the initial antibiotic failed. In 12 of these patients (five in the ceftazidime group and seven in the ciprofloxacin group) SBP resolved after the antibiotic therapy was changed. In 12 of these patients (five from the ceftazidime group and seven from the ciprofloxacin group) SBP resolved after changing the antibiotic therapy. In the five patients from the ceftazidime group in whom SBP resolved after changing antibiotic therapy, the effective antibiotics administered were teicoplanin and imipemen in four patients and teicoplanin, aztreonam and metronidazole in one patient. In the seven patients from the ciprofloxacin group in whom SBP resolved after changing antibiotic therapy, the effective antibiotics administered were teicoplanin and imipemen in three patients, teicoplanin and meropenem in three patients and clindamycin, aztreonam and metronidazole in one patient. Therefore, according to intention-to-treat analysis, the resolution of SBP occurred in 51 patients (93%) initially assigned to receive ceftazidime and 56 (92%) of those initially assigned to receive ciprofloxacin.

Table 2.  Reasons for failure of the assigned antibiotic treatment
 Ceftazidime (n = 55)Ciprofloxacin (n = 61)
  1. PMN, polymorphonuclear leucocytes.

Duration of global treatment (days)88
Duration of oral treatment (days)5.14 ± 0.14
No positive response, n (%)5 (9.1)7 (11.5)
No improvement in clinical signs of infection21
No significant reduction in ascitic fluid PMN count at 48 h24
No sensitivity of bacteria isolated from ascitic fluid to the assigned antibiotic treatment12
Adverse effects, n (%)1 (1.8)2 (3.3)
Recurrence of infection, n (%)1 (1.8)2 (3.3)
Superinfections, n (%)2 (3.6)1 (1.6)
Total, n (%)9 (16.4)12 (19.7)

The intravenous–oral step-down schedule was possible in 50 of the 61 patients (82%) randomized to receive ciprofloxacin. Mean time from the starting of intravenous ciprofloxacin to oral step down was 5.14 ± 0.14 days. It was impossible to implement the intravenous–oral step-down schedule in 11 patients for the following reasons: grades II–IV hepatic encephalopathy (six patients), ileus (three patients), more than one reason (two patients). Switch therapy in the ciprofloxacin group made it possible to discharge 45 of 61 patients (74%) before the day 8 of antibiotic treatment and to be completed at home. As a consequence, as reported in Table 4, hospital stay was significantly shorter in the ciprofloxacin group than in the ceftazidime group (8 ± 0.7 vs. 14 ± 0.6 days, P < 0.001).

Table 4.  Hospital stay and relative cost per patient according to the assigned antibiotic treatment
 CeftazidimeCiprofloxacin
One-day cost of hospital stay (in €)[mean hospital stay per patient (days)]Costs of hospitalization per patient (in €)[mean hospital stay per patient (days)]Costs of the hospitalization ‘per’ patient (in €)
  1. a In the analysis of the cost of hospital stay, type 1 HRS, GI haemorrhage and hepatic encephalopathy were considered as complications of SBP; when two or more complications occurred at the same time the most expensive was considered; the cost of diagnostic and therapeutic procedures for each complication was not included in the analysis.

  2. P < 0.001 in the comparison between the two groups.

  3. SBP, spontaneous bacterial peritonitis; HRS, hepatorenal syndrome; GI, gastrointestinal.

SBP without complicationsaN = 39N = 39N = 49N = 49
 Hepato/gastroenterology (177)11 ± 0.71933 ± 1215.5 ± 0.3*1023 ± 58*
SBP with complicationsaN = 16N = 16N = 12N = 12
 Hepato/gastroenterology
  Type 1 HRS (289)1.9 ± 0.5546 ± 1541.3 ± 0.4365 ± 125
  Encephalopathy (311)0.4 ± 0.2130 ± 480.4 ± 0.2122 ± 57
  GI haemorrhage (478)0.2 ± 0.1104 ± 600.3 ± 0.2157 ± 82
 Intensive care unit (948)0.5 ± 0.2431 ± 1750.4 ± 0.2328 ± 143
Total14 ± 0.63145 ± 2368.0 ± 0.7*1994 ± 284*

Complications and mortality during hospitalization

The most frequent clinical complications that developed in patients in the ceftazidime and ciprofloxacin groups during the treatment of SBP are shown in Table 3. Seven patients in the ceftazidime group and four in the ciprofloxacin group died during hospitalization.

Table 3.  Complications and clinical outcome according to the assigned antibiotic treatment
 CeftazidimeCiprofloxacin
  1. aThree patients excluded in each group because they underwent liver transplantation within 3 months of inclusion.

  2. HRS, hepatorenal syndrome; MOF, multiorgan failure.

Patients with complications20 (36)14 (23)
Renal failure, n (%)16 (29)13 (21)
Onset of renal failure, n (%)7 (13)3 (4.9)
Further impairment of pre-existing renal failure, n (%)9 (16)10 (16)
Type 1 hepatorenal syndrome, n (%)11 (20)8 (13)
Peak value of serum urea (mg/dL)79 ± 9.066 ± 5.9
Peak value of serum creatinine (mg/dL)1.8 ± 0.21.5 ± 0.1
Peak reduction of creatinine clearance (mL/min)45 ± 2.447 ± 2.6
Peak reduction of 24-h urine volume (mL)972 ± 651036 ± 61
Peak reduction of 24-h urinary Na excretion (mmol)43 ± 3.343 ± 3.1
Worsening of hepatic failure, n (%)11 (20)6 (9.8)
With hepatic encephalopathy, n (%)9 (16)6 (9.8)
Gastrointestinal haemorrhage, n (%)3 (5.5)3 (4.9)
Deaths during hospitalization, n (%)7 (13)5 (8.2)
Causes of death during hospitalization
 Type 1 HRS32
 MOF21
 Terminal liver failure12
 Gastrointestinal haemorrhage10
 Deaths at 3 months, n (%)12 (23)a8 (14)a
Causes of death during follow-up
 Terminal liver failure31
 Gastrointestinal haemorrhage11
 Type 1 HRS10
 Pneumonia01

Twelve of the 19 patients (63%) who developed type 1 HRS showed a complete response to treatment with terlipressin and albumin, two showed a partial response (11%) and five showed no response (26%). Six of 19 patients (32%) who developed type 1 HRS died during hospitalization (one partial responder and five non-responders). One patient underwent liver transplantation during hospitalization.

The PMN count in ascitic fluid (P < 0.001), PMN count in blood (P < 0.001), serum urea (P < 0.0025), creatinine clearance (P < 0.01) and total serum bilirubin at admission (P < 0.025) were found to be significantly associated with in-hospital survival. In the multivariate analysis only the PMN count in ascitic fluid (goodness-of-fit = 34.815, coefficient = 0.0299, SE coefficient = 0.0073, P < 0.001) independently correlated with in-hospital survival.

Economic analysis of SBP treatment

The mean cost of antibiotic treatment per patient was significantly lower in the ciprofloxacin group than in the ceftazidime group (150.70 ± 7.28 vs. 291.83 ± 12.22 €, P < 0.001), representing a saving of 141.13 € per patient. The mean cost of hospital stay according to clinical course of SBP is shown in Table 4. The mean total saving per patient in the ciprofloxacin group was 1291.38 €.

Complications and mortality at 3 months

During the 3-month follow-up period six of 105 patients who had been discharged from hospital after the resolution of SBP underwent liver transplantation and were excluded from the analysis of the 3-month mortality rate. Eight of the remaining 99 patients died, five in the ceftazidime group and three in the ciprofloxacin group. As a consequence, the mortality rate at 3 months was 23% in the ceftazidime group and 14% in the ciprofloxacin group (P = N.S.).

Among patients who developed a type 1 HRS as a consequence of SBP, type 1 HRS recurred in three of the 12 remaining patients (25%) and a complete response after retreatment was observed in two. Two patients died during follow-up: causes of death were recurrent type 1 HRS (one patient) and GI haemorrhage and terminal liver failure (one patient). The mortality rate at 3 months was 44% among those patients who developed type 1 HRS as a consequence of SBP and 13% among those who did not (P < 0.01). Excluding patients who underwent liver transplantation during the 3-month follow-up period, mean transplant-free survival in complete responders to terlipressin and albumin was 230 ± 61 days, while in partial responders and non-responders it was 16.6 ± 3.3 days (P < 0.05). The only independent predictor of survival in patients who developed type 1 HRS was the Child-Pugh-Turcotte score (goodness-of-fit = 6.161, coefficient = 0.335, SE coefficient = 0.144, P < 0.0025).

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

In 1996, Navasa et al. proved that the oral administration of a quinolonone, ofloxacin, was as effective as a third-generation cephalosporin, cefotaxime, in the treatment of uncomplicated SBP in cirrhotic patients with ascites.18 In 2000, Terg et al. showed on the basis of an uncontrolled study that a switch therapy with ciprofloxacin was as effective as intravenous ciprofloxacin in the treatment of complicated and uncomplicated SBP.17 On the basis of these studies, it was hypothesized for the patients with SBP to be discharged from hospital before the end of the treatment with quinolone and for the treatment to be completed orally at home.18 Nevertheless, this hypothesis has never been tested in a controlled clinical trial up to now. In the present study, we compared switch therapy with ciprofloxacin, consisting of administration of the drug first intravenously and then orally, to intravenous ceftazidime in the treatment of SBP in cirrhotic patients with ascites. Based on one of the largest series of patients with SBP ever published up to now, our results support the hypothesis that switch therapy with ciprofloxacin is as effective as the intravenous administration of ceftazidime in the treatment of SBP. To our knowledge, this is the first report in which the sample size has been calculated in a study on the treatment of SBP in cirrhosis. Nevertheless, it must highlighted that the sample size was calculated not only on the hypothesis of a similar effectiveness between the two antibiotic treatments but also on a potential (different) length of hospitalization as a consequence of the oral step down in the ciprofloxacin group. It is clear that a larger number of patients should have been enrolled in order to evidence statistically that the two antibiotic treatments are quite equally effective in this clinical scenario. With this limitation, our study supports the hypothesis that switch therapy with ciprofloxacin is more cost-effective than intravenous ceftazidime in the treatment of SBP because it is cheaper. Initially the mean cost of antibiotic treatment per patient was 151.94 ± 7.23 and 291.83 ± 12.22 € in the ciprofloxacin and ceftazidime groups respectively (P < 0.001). Moreover, switch therapy with ciprofloxacin allowed the discharge of most patients before the end of treatment and shortened the length of hospital stay by about 42%. In Italy, this results in a mean saving per patient of 1150.25 €. Adding together the saving due to the different costs of antibiotic treatment and that due to the different length of hospital stay the mean total saving per patient in the ciprofloxacin group turned out to be 1291.38 €. In order to reinforce the clinical relevance of these results it should be observed that the mean length of hospital stay in the ceftazidime group in our study was quite the same as that observed in Spain by Sort et al. treating the patients with another third-generation cephalosporin,25 and by Thuluvath et al. in the US.37 The gap between the length of hospital stay and the duration of antibiotic treatment in our study as well as in previous ones16, 18, 25 is not surprising because it is related to the common development of complications in cirrhotic patients treated for SBP.

It should be underlined that our results were obtained in patients who were not on prophylaxis with norfloxacin for a previous episode of SBP. In fact, there is evidence to prove that patients who follow a selective intestinal decontamination with norfloxacin may develop infections caused by quinolone-resistant bacteria.38, 39 Therefore, in order to give a clear clinical message, we proposed switch therapy with ciprofloxacin only for the treatment of the first episode of SBP in cirrhotic patients with ascites. The intravenous–oral step-down schedule with ciprofloxacin can be safely performed soon after the resolution of some complications of SBP such as hepatic encephalopaty, ileus, vomiting and/or diarrhoea.

The second relevant result of our study is that the overall in-hospital mortality because of SBP was the lowest value ever observed in patients who were treated only with antibiotics (10%).9–14, 16–18

It has been observed that almost one-third of cirrhotic patients with ascites and SBP develop renal failure and that in almost half of them renal failure has the features of type 1 HRS. In addition, renal failure was found to be a common cause of death in these patients.20–22 In keeping with this evidence, the prevalence of renal failure and type 1 HRS in our patients were 25% and 16.4% respectively. Nevertheless, in 79% of these patients it was possible to completely restore renal function by means of a new therapeutical option namely the intravenous administration of terlipressin and albumin.28, 29 Patients with a complete response to terlipressin and albumin survived longer than those who had partial or no response. The successful treatment of type 1 HRS contributed towards reducing the overall in-hospital rate because of SBP in our series of patients to such an extent that, in contrast with previous studies,5, 18, 24, 40 renal failure was not found to be an independent predictive factor of death in these patients. As a consequence, among the predictors of death highlighted in previous studies,5, 18, 24, 40 only the severity of infection was confirmed in our series. The overall in-hospital mortality rate because of SBP in our study is quite close to that observed by Sort et al. in cirrhotic patients with SBP treated with albumin in addition to cefotaxime (10%).25 Our study was planned before the publication of the study of Sort et al.25 so we did not use albumin to prevent HRS. While we agree on the need to prevent SBP-induced type 1 HRS, we believe that terlipressin and albumin will be an important therapeutic option in patients in whom prevention fails.

In conclusion, we observed that switch therapy with ciprofloxacin is more cost-effective than intravenous ceftazidime in the treatment of SBP in cirrhotic patients who are not on prophylaxis with quinolones as it is considerably cheaper because the therapy could be completed at home. SBP-induced type 1 HRS may be effectively treated by terlipressin and albumin in order to reduce the mortality rate due to the infection.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

The authors thank Mr Duccio Schiavon for the statistical analysis and Ms Helene Lown and Ms Marina Canapero for the preparation of the manuscript.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
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    Wyke RJ. Problems of bacterial infection in patients with liver disease. Gut 1987; 28: 62341.
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